Cationic liposomes have been successfully employed to transfect cells in vitro with DNA, RNA, and oligonucleotides. However, cationic liposomes have a low intrinsic transfection efficiency and a number of cell types are relatively refractory to liposome-mediated transfection. A major issue with cationic liposome transfection is release of the transfection complex into the cytosol rather than degradation via the phagolysosomal pathway. Resistance to transfection may also be the result of poor endocytosis of the transfection complex secondary to bypass of receptor-mediated internalization. The investigators propose to address these issues by two methods. The first is to incorporate a pH sensitive fusogen into the transfection complex to enhance DNA transfer to the cytosol. The second is to develop a net-anionic liposome DNA complex that carry surface recognition moieties such as CD4-binding peptides. Successful completion of this project will result in the generation of novel "universal" transfection systems as well as of target-cell specific transfection systems for cells that are poorly transfected with conventional systems. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE